A Novel COL7A1 Mutation in a Chinese Family with Epidermolysis Bullosa Pruriginosa.

BACKGROUND: Epidermolysis bullosa pruriginosa (DEB-Pr) is a rare disease caused by mutations in the collagen, type VII, alpha 1 (COL7A1) gene. Here, we identified a novel COL7A1 mutation in a Chinese family with DEB-Pr. METHODS: Blood samples were obtained from 4 affected individuals of the 16-member family for isolation of genomic DNA. The COL7A1 exons were then amplified using PCR for direct sequencing. Two unaffected family members and 50 healthy controls were also enrolled for a comparison of genetic polymorphisms. RESULTS: We identified a novel mutation, exon 110 c.8111G>A, P.Gly2704Glu (GGA>GAA), in all 4 affected individuals but not in the unaffected family members or healthy controls. CONCLUSIONS: A glycine substitution specific to COL7A1, exon 110 c.8111G>A, P.Gly2704Glu (GGA>GAA), was identified in a Chinese family with DEB-Pr.

Identical glycine substitution mutations in type VII collagen may underlie both dominant and recessive forms of dystrophic epidermolysis bullosa.

Autosomal dominant and recessive forms of dystrophic epidermolysis bullosa (DEB) result from mutations in the type VII collagen gene (COL7A1). Although paradigms have emerged for genotype/phenotype correlation in DEB, some pathogenic mutations in COL7A1, notably glycine substitutions within the type VII collagen triple helix, may lead to diagnostic difficulties, since certain glycine substitutions can result in either dominant or recessive mutant alleles. Delineation of glycine substitution mutations into two discrete groups, however, is made difficult by observations that, for some particular glycine substitutions in type VII collagen, the same mutation can result in both dominant and recessive disease. In this report we describe four further glycine missense mutations: p.Gly1483Asp, p.Gly1770Ser, p.Gly2213Arg and p.Gly2369Ser, which can lead to either dominant or recessive DEB, and which result in a spectrum of clinical abnormalities. We also identify a further 30 new glycine substitution mutations that cause either dominant or recessive DEB, but not both. In screening the COL7A1 gene for mutations in individuals with DEB our data highlight that delineation of glycine substitutions in type VII collagen has important implications for genetic counselling.

Haplotypic classification of dystrophic epidermolysis bullosa in Tunisian consanguineous families: implication for diagnosis.

Dystrophic epidermolysis bullosa (DEB) is a rare genodermatosis caused by mutations in the type VII collagen gene COL7A1. Clinical diagnosis of DEB should be confirmed by histopathological and electron microscopy analysis, which is not always accessible. We report here a genetic investigation of DEB consanguineous families in Tunisia. A total of 23 EB families were genotyped with 5 microsatellite markers overlapping the COL7A1 gene. Among these families, 19 presented with the dystrophic form of EB, 9 were diagnosed by histopathological examination, 2 had the simplex form, 1 had a junctional EB, and 1 was affected by an unclassified form of EB. The informativeness of the markers was studied and allowed us to select three markers for genetic testing of DEB in Tunisian families at risk. Haplotype analysis and homozygosity by descent suggest that all families classified clinically as having DEB and the patient who presented with an unclassified form of EB are likely linked to the COL7A1 gene, and showed evidence for exclusion for the simplex and junctional cases. For COL7A1 linked families, two main haplotypes were shared by eight families. For all the other cases, haplotypic heterogeneity was observed, thus suggesting a mutational heterogeneity among Tunisian DEB families. The genetic results matched with the ultrastructural analysis in all the DEB families and with the clinical examination in 94.7% of all studied DEB families. This study is to our knowledge the first genetic investigation of DEB in the Maghrebian population. We propose a selection of informative markers and show the importance of haplotype analysis as a relatively easy and cost and time effective method for carrier screening and prenatal diagnosis of DEB in consanguineous families at risk.

Differences in recurrent COL7A1 mutations in dystrophic epidermolysis bullosa: ethnic-specific and worldwide recurrent mutations.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the gene encoding type VII collagen (COL7A1). Although most COL7A1 mutations are unique to individual families, small numbers of mutations are recurrent. The recurrent mutations R578X, 7786delG, and R2814X seem to be exclusive to a specific ethnic group, the British population. The mutations 5818delC, 6573+1G-->C, and E2857X are present only in individuals of Japanese ethnic origin. On the other hand, the mutations 425A-->G and G2043R have been found in several different ethnic groups. The purpose of this study was to clarify whether these recurrent mutations are also found in patients of other ethnic groups with DEB, mainly Asian patients. We demonstrated the absence of the recurrent mutations R578X, 7786delG, and R2814X in 42 non-British patients with DEB and detected the mutations 425A-->G in a French patient and G2043R in Japanese and Chinese patients with DEB. The mutations 5818delC, 6573+1G-->C, and E2857X were detected in 11 Japanese patients (13 alleles) with DEB. Our results confirm that R578X, 7786delG, and R2814X mutations are specifically limited to British patients, and the mutations 5818delC, 6573+1G-->C, and E2857X are frequent in Japanese patients. On the other hand, the mutations 425A-->G and G2043R can be found in different ethnic groups. In conclusion, our results further support the notion that recurrent mutations can be classified into two types, ethnic-specific mutation and worldwide mutation.

A new glycine substitution mutation in the COL7A1 gene in a Chinese family with dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils. The characteristic genetic lesion in dominant DEB (DDEB) is a glycine substitution in the collagenous domain of the protein. In this study, we identified a Chinese family with a four-generation pedigree of DDEB, in whom a novel glycine substitution mutation in COL7A1 was demonstrated. A heterozygous nucleotide G-->A transition at position 6208 in exon 74 of COL7A1 was detected, which resulted in a glycine to arginine substitution (G2070R) in the triple-helical domain of type VII collagen. This substitution was not found in 110 unrelated normal alleles. This report emphasizes the predominance of glycine substitution mutations in DDEB and contributes to the expanding database on COL7A1 mutations.

A glycine-to-arginine substitution in the triple-helical domain of type VII collagen in a family with dominant dystrophic epidermolysis bullosa pruriginosa.

Epidermolysis bullosa pruriginosa is a recently recognized variant of dystrophic epidermolysis bullosa (DEB) characterized by severe pruritus and scarring, mainly involving the extensors of the extremities. In this study, we searched for mutations in the type VII collagen gene (COL7A1) using polymerase chain reaction amplification of exonic segments of COL7A1, followed by heteroduplex analysis, in a Chinese pedigree with dominant DEB displaying a striking anastomosing network of lichenoid papules and scarring. The study revealed a G-to-A transition at nucleotide 6724 within exon 85 of COL7A1, converting a glycine to an arginine (G2242R) within the triple-helical domain of the type VII collagen in affected individuals. These findings demonstrate that EB pruriginosa in this family is a clinical variant of dominant DEB.

Heterogeneous reactivity with LH7.2 and the first prenatal diagnosis of generalized recessive dystrophic epidermolysis bullosa among Japanese patients.

BACKGROUND: The heterogeneity of abnormal patterns of expression of type VII collagen in the skin of Japanese patients with generalized recessive dystrophic epidermolysis bullosa (g-RDEB) remains unclear, and the prenatal diagnosis of this condition has not yet been performed in Asia. OBJECTIVE: The present study was performed to clarify patterns of abnormal expression of type VII collagen among Japanese patients with g-RDEB, and to evaluate the first application of prenatal diagnosis for this condition in an Asian country. METHODS AND RESULTS: Only 2 of 8 Japanese patients with g-RDEB evaluated demonstrated a complete absence of type VII collagen at the skin basement membrane zone when tested with an LH7.2 monoclonal antibody. The other 6 patients revealed present, although diminished, LH7.2 reactivity. The mother of 1 patient who lacked reactivity to the LH7.2 monoclonal antibody sought prenatal diagnosis. Electron microscopy of fetal skin specimens obtained at 19 weeks' gestation showed mature anchoring fibrils with no separation of the dermis and epidermis. Indirect immunofluorescence revealed normal expression of type VII collagen. The fetus was diagnosed as being unaffected, and a normal female infant was delivered at 38 weeks' gestation. CONCLUSION: Our findings indicate a lower incidence of the negative expression of LH7.2 epitope in the type VII collagen among Japanese rather than non-Japanese patients with g-RDEB. However, LH7.2 still serves as a reliable diagnostic probe under certain conditions such as the diagnosis and prenatal diagnosis of g-RDEB as in the present case.